title: A 2,6,9-hetero-trisubstituted purine inhibitor exhibits potent biological effects against multiple myeloma cells.
abstract: A focused library of hetero-trisubstituted purines was developed for improving the cell penetrating and biological efficacy of a series of anti-Stat3 protein inhibitors. From this SAR study, lead agent 22e was identified as being a promising inhibitor of MM tumour cells (IC50's <5μM). Surprisingly, biophysical and biochemical characterization proved that 22e was not a Stat3 inhibitor. Initial screening against the kinome, prompted by the purine scaffold's history for targeting ATP binding pockets, suggests possible targeting of the JAK family kinases, as well for ABL1 (nonphosphorylated F317L) and AAK1.
authors.affiliation: Department of Chemistry, University of Toronto, 3359 Mississauga Road North, Mississauga, ON, L5L 1C6, Canada.
authors.forename: Vijay M
authors.initials: VM
authors.lastname: Shahani
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Ball
authors.forename: Allan V
authors.initials: AV
authors.lastname: Ramos
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Li
authors.forename: Paul A
authors.initials: PA
authors.lastname: Spagnuolo
authors.forename: Sina
authors.initials: S
authors.lastname: Haftchenary
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schimmer
authors.forename: Suzanne
authors.initials: S
authors.lastname: Trudel
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Gunning
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C587056:2-(2-((4-cyclohexylbenzyl)amino)-6-((4-fluorophenyl)amino)-9H-purin-9-yl)ethyl sulfamate; D000970:Antineoplastic Agents; D011687:Purines; D050796:STAT3 Transcription Factor; D013449:Sulfonamides; D000241:Adenosine
keywords: Cancer therapeutics; Kinome; Multiple myeloma; Purine scaffold; Stat3